Chronic myelogenous leukemia (CML) is a disease having clinical and pathological features distinct from those of other forms of leukemia. It is widely accepted that the cause of CML is a specific chromosomal translocation between human chromosome 9 and human chromosome 22. The N chromosome resulting from this translocation is commonly referred to as the Philadelphia chromosome. Darnell, J. et al., Molecular Cell Biology, 2nd Ed., W. H. Freeman and Co., New York (1990), p. 992. The gene for c-abl (ABL), a tyrosine kinase thought to be involved in growth control, resides on the distal arm of human chromosome 9, while the gene for c-bcr (BCR) resides on human chromosome 22. The translocation places the promoter distal three exons of ABL, including those elements which encode the tyrosine kinase domain, downstream of either the first or second exon of BCR. Chung, S. and Wong, P. M. C., Oncogene, 10:1261-1268 (1995). The product of the translocation between human chromosome 9 and human chromosome 22 is a chimeric gene, BCR-ABL, which encodes a fusion protein, often referred to as p185.sup.bcr-abl or p210.sup.bcr-abl, depending upon the inclusion of the second exon of BCR. Bartram, C. R., et al., Nature, 306:277-280 (1983). p185.sup.bcr-abl causes acute leukemia, typically lymphoblastic; p210.sup.bcr-abl usually causes CML, but can occasionally also cause acute leukemia.
Compared to normal c-abl, bcr-abl has increased tyrosine kinase activity. Konopka, J., et al., Cell, 37:1035-1042 (1984). Additionally, c-abl, as a non-receptor tyrosine kinase, functions both in the nucleus and the cytoplasm and bcr-abl functions exclusively in the cytoplasm. These two characteristics of bcr-abl are essential elements of its transforming abilities. McWhirter, J. R., et al., Mol. Cell Bio., 11:1553-1565 (1991).
Following this chromosomal translocation within a single, primitive myeloid stem cell, the progeny of the affected cell gradually populate the entire intermediate and late hematopoietic maturational compartments. Despite the presence of the Philadelphia chromosome, these progeny, referred to as Ph.sup.+ cells, are able to differentiate and mature along the various myeloid lineages while retaining the capacity to function as their normal, unaffected counterparts. Invariably, in an average span of three to five years, the disease progresses into a malignant stage known as blast crisis. The affected cells acquire additional chromosomal abnormalities and lose their ability to differentiate and mature, resulting in the functional breakdown of the hematopoietic system. Clarkson, B. and Strife, A., Leukemia, 7:1683-1721 (1993). Daley, G. Q. and Ben Neriah, Y., Adv. Cancer Res., 57:151-184 (1991). Deisseroth, A. B. and Arlinghaus, R. B., eds. Chronic Myelogenous Leukemia-Molecular Approaches to Research and Therapy, New York, Marcel Dekker (1991). Sawyers, C. L. et al., Cell, 64:337-350 (1991).
Clinical treatment of CML has remained essentially unchanged for many years. To date, with the exception of marrow ablative chemotherapy and/or total body irradiation followed by allogeneic bone marrow transplantation, no effective cure has been developed for the disease. Only a minority of CML patients have been cured by complete bone marrow transplantation. Treatment with alpha interferon has led to durable remissions in about 10-20% of chronic phase patients, but longer follow-ups are necessary to determine if these patients will have late relapses. In light of this, the need for better treatment methods is apparent.